CN1364092A - Methods and compositions using (+) norcisapride in combination with proton pump inhibitors or H2 receptor antagonists - Google Patents

Methods and compositions using (+) norcisapride in combination with proton pump inhibitors or H2 receptor antagonists Download PDF

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CN1364092A
CN1364092A CN00806999A CN00806999A CN1364092A CN 1364092 A CN1364092 A CN 1364092A CN 00806999 A CN00806999 A CN 00806999A CN 00806999 A CN00806999 A CN 00806999A CN 1364092 A CN1364092 A CN 1364092A
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optical voidness
proton pump
cisapride
stereoisomer
pump inhibitor
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P·D·鲁宾
T·J·巴贝里希
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Sunovion Pharmaceuticals Inc
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Sepracor Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

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Abstract

The invention relates to methods and compositions for the prevention, treatment, or management of gastrointestinal disorders or symptoms thereof, employing two or more agents or compounds to provide a triple site action on 5-HT3 receptors, 5-HT4 receptors, and at least one of H2 receptors and proton pumps.

Description

Using (+) norcisapride in combination and proton pump inhibitor or H 2The method and composition of-receptor antagonist
1. invention field
The present invention relates to prevent, treat and control the method and composition of gastroenteropathy or its symptom, it is by taking simultaneously or act in order 5-HT 3Receptor, 5-HT 4Receptor and H 2One or more reagent or the chemical compound of receptor or proton pump.
2. background of invention
Gastroenteropathy is to influence the common disease that gastrointestinal tract is the harmonization of the stomach intestinal.Many gastroenteropathys are arranged, and it comprises: gastroesophageal reflux disease, vomiting, gastrointestinal movement sexual disorder, gastrointestinal ulceration, pathology supersecretion disease and hyperchlorhydria.These diseases can be treated by various Noninvasive modes, for example: take therapeutic agent to the patient, for example ZANTAC  (ranitidine), TRITEC  (ranitidine), AXID  (ZL-101), TAGAMET  (cimetidine), PREVACID  (lansoprazole), PEPCID , PEPCID AC , ACID CONTROLLER T M, MYLANTA AR ACID REDUCER T M(famotidine), PRILOSEC  (omeprazole) and other medicine.New medicinal compound and preparation just constantly are developed.
U.S. Pat 4,962,115,5,057,525 and 5,137,896 (being " VanDaele " invents) disclose N-(3-hydroxy-4-piperidinyl thiazolinyl) benzamide compound.The allegedly motion of these chemical compounds energy stimulating gastrointestinal road systems.Van Deale points out: can obtain the cis and the trans diastereomer racemate of these chemical compounds by conventional method independently, these cis and trans diastereomer racemate can further split into its optical isomer.One of this racemic modification is a cisapride, and its chemistry is called suitable-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy) propyl group]-3-methoxyl group-4-piperidyl]-the 2-methoxy benzamide.ScHapira etc., Acta Gastroenterolog.Belg., LIII:446-457 (1990).Cisapride mainly is used to treat gastroesophageal reflux disease (" GERD "), and this disease is characterised in that the anti-esophagus that flow to of material in the stomach.The commercially available prod of cisapride is PROPULSID , and it is the racemic mixture along (-) and suitable (+) cisapride diastereomer.
Thereby heterocyclic carbamate derivatives has some significant pharmacotoxicological effects owing to act on the nervous system of being regulated by the neurotransmitter serotonin.It is reported: the enterochromaffin cell that the main generation of serotonin and storing position are gastrointestinal mucosa.Also it is reported in addition: serotonin provides powerful intestinal transmission and reduces soak time, and usually concurrent diarrhoea.This stimulation is also usually relevant with nausea and vomiting.
Owing to can regulate the serotonin nervous system in gastrointestinal tract, some heterocyclic carbamate derivatives are effective anti-antiemetic, and are used in cancer chemotherapy or radiation period control vomiting.Costall etc., NeuroPharmacology, 26:1321-1326 (1987).This effect is it at specific part 3-type 5-hydroxy tryptamine (5-HT particularly 3) result of receptor blocking serotonin ability.Clarke etc., Trends in Pharmacological Science, 10:385-386 (1989).Chemotherapy and radiation can cause nausea and vomit by enterochromaffin cell in the infringement gastrointestinal tract.As a result, the neurotransmitter serotonin is released, and stimulates afferent vagus nerve fiber (therefore causing the anti-stream of vomiting) and serotonin receptor in the chemoceptor trigger area in brain postrema zone.It is not immediately clear the region of anatomy of this effect of heterocyclic carbamate derivatives, also unclear this effect is maincenter (CNS) effect or peripheral action or its combination.Barnes etc., J.Pharm.Pharmacol., 40:586-588 (1988).
Second kind of some heterocyclic carbamate derivatives obviously effect be to increase the gastrointestinal smooth muscle activity from esophagus to nearly small intestinal zone, thereby quicken esophagus and small intestinal transmission and help gastric emptying and increase the lower esophageal sphincter tonicity.Decktor etc., Eur.J.Pharmacol., 147:313-316 (1988).Though heterocyclic carbamate derivatives itself does not belong to the cholinoceptor antagonist, foregoing smooth muscle effect can by the M-ChR blocker for example atropine or the neurotransmission inhibitor Fugu ocellatus toxin of for example blocking the sodium channel block.Fernandez and Massingham, Zife Sci., 36:1-14 (1985).Reported the similar blocking-up of serotonin contractive effect in the small intestinal active already.Craig and Clarke, Brit.J.Pharmacol., 96:247P (1989).Someone thinks: the main smooth muscle effect of some heterocyclic carbamate derivatives is that a class is called 5-HT 4The result of the serotonin receptor agonism of receptor, 5-HT 4Receptor is positioned at intestinal wall myenteric plexus relay cell surface.Clarke etc., Trends inPharmacological Science, 10:385-386 (1989) and Dumuis etc., N.S.Arch.Pharmacol., 340:403-410 (1989).The activation of these receptors increases acetylcholine from being positioned near the release of the parasympathetic nervous end the smooth muscle fiber on every side then.Just really cause muscle contraction just because of acetylcholine and its receptors bind on level and smooth sarolemma surface.
It is reported that cisapride enters the central nervous system, and and 5-HT 4Receptors bind.This means that cisapride may have the maincenter regulating action.Cisapride is effective 5-HT 4Receptors ligand, and this receptor is positioned at central nervous system's several regions.Dumuis etc., N.S.Arch.Pharmacol., 340:403-410 (1989).Regulate serotonergic systems and may have multiple behavior effect.
To make liver that the metabolism of cisapride is produced inhibition racemic cisapride and other therapeutic agent administering drug combinations.For example, ketoconazole has tangible influence to the kinetics of cisapride, because its metabolism that suppresses cisapride is eliminated, causes Cpss to increase by 8 times.Physician ' s Desk Reference , Medical Economics Co., Inc., P.1308-1309 the page or leaf, the 52nd edition (1998).Raceme cisapride and other therapeutic agent interact and also can cause potential cardiovascular side effects, for example cardiotoxicity.When thereby other medicines in the patient body disturb the metabolism of cisapride to cause the accumulation of inside and outside racemization cisapride, this potential side effect can take place.
These interactions become the remarkable defective of using the raceme cisapride; Particularly, owing to before the another kind of therapeutic agent of being everlasting, use the raceme cisapride simultaneously or after following closely, more have this defective.In addition, take the raceme cisapride to the people and also find to cause for example arrhythmia of side effect, comprise ventricular tachycardia, ventricular fibrillation, QT prolongation and torsades de pointers, central nervous system (" CNS ") effect, increase systolic pressure, interact with other medicines, diarrhoea, abdominal cramps and heart fail.
The aryl hydroxylating mainly takes place by the oxidation N-dealkylation reaction of piperidines nitrogen-atoms or on by 4-fluorophenoxy or Benzoylamide ring in the intravital metabolic pathway of people in the raceme cisapride.Meuldermans etc., Drug Metab.Dispos., 16 (3): 410-419 (1988); With Drug Metab.Dispos. such as Meuldermans, 16 (3): 403-409 (1988).Cisapride (Norcisapride) falls, chemistry 4-amino by name-5-chloro-N-(3-methoxyl group-4-piperidyl)-2-methoxy benzamide, and it is the active metabolite of cisapride.
Recently, the researcher report is arranged: optical voidness (+) stereoisomer that cisapride falls in the cisapride metabolite has many useful characteristics, and does not have the side effect of some raceme cisapride.Especially, United States Patent (USP) 5,739,151 disclose Application Optics pure (+) falls the method that cisapride produces antiemetic effect and other disease of treatment.
Be studied other reagent or the chemical compound that are used for the treatment of gastroenteropathy and comprised proton pump inhibitor and H 2Receptor antagonist.Proton pump inhibitor is by suppressing H +-K +Thereby the ATP enzyme is regulated gastric acidity and is treated gastroenteropathy.H 2Receptor antagonist suppresses histamine and H 2Thereby gastric acid secretion is regulated in the combination of receptor.Goodman ﹠amp; Gilman, The Pharmacological Basisof Therapeutics, the 9th edition, 901-915 page or leaf (1996).
The acid concentration graded of cross-cell membrane is bigger.Greatest gradient may be present in the gastric parietal cell plasma membrane both sides that secretion hydrochloric acid enters gastric juice in the body.Because concentration of hydrochloric acid can be up to 0.1M in the gastric juice, the H in the cell +Concentration about 10 -7M, parietal cell can be under about 100 ten thousand to 1 Concentraton gradient environment reverse secretion H +Ion.A kind of H that is called +-K +The membrane bound enzyme of ATP enzyme can help H +Contrary Concentraton gradient transmembrane transport is with exchange K +Thereby formation gastric hydrochloric acid.Per molecule Cell sap ATP is hydrolyzed into ADP and phosphate can be 2H +Ion from the Cell sap transmembrane transport to stomach.Goodman﹠amp; Gilman, The Pharmacological Basis of Therapeutics, the 9th edition, 901-915 page or leaf (1996).
The H that suppresses parietal cell secretion surface by specificity +-K +ATP enzyme system, proton pump inhibitor can suppress last step-gastric acid secretion that acid generates.Proton pump inhibitor comprises benzimidazole compound, for example omeprazole (PRILOSEC ), lansoprazole (PREVACID ) and pantoprazole.These proton pump inhibitors contain sulfinyl, and this group is between the benzimidazole and piperidine ring of replacement.Under the neutral pH environment, omeprazole, lansoprazole and pantoprazole are chemically stable, fat-soluble weak base, do not suppress active.These uncharged weak base are transported to parietal cell from blood, and redispersion is in secretory tubyle, thereby medicine is hunted down by protonated herein.These protonated materials are reset and are formed sulfenic acids and sulfenamide, latter's energy and H +-K +The sulfydryl of ATP enzyme interacts.When per molecule enzyme and two molecule inhibitors were had an effect, this enzyme was just restrained fully.The effect specificity of proton pump inhibitor is considered to derive from: a) H +-K +The selectivity of ATP enzyme distributes; B) generation of catalytic reaction inhibitor needs sour environment; And c) in acid canuliculi environment and contiguous target protonated medicine of enzyme areas captured and cation sulfenamide.Goodman ﹠amp; Gilman, The PharmacologfcalBasis of Therapeutics, the 9th edition, 901-915 page or leaf (1996).
H 2Receptor antagonist competitive inhibition histamine and H 2The interaction of receptor.They are high selectivities, to H 1Receptor does not almost have or not effect.Though H 2Receptor is present in many tissues and comprises in blood vessel and the bronchial smooth muscle, but except that influencing gastric acid secretion, H 2Receptor antagonist does not almost completely disturb physiological function.H 2Receptor antagonist comprises ZL-101 (AXID ), ranitidine (ZANTAC  and TRITEC ), famotidine (PEPCIDAC ) and cimetidine (TAGAMET ).Goodman ﹠amp; Gilman, The Pharmacological Basis ofTherapeutics, the 9th edition, 901-915 page or leaf (1996).
H 2Receptor antagonist suppresses by histamine, other H 2The gastric acid secretion that agonist, gastrin and muscarinic agonist (degree is lower) cause.H 2Receptor antagonist also suppresses the acid secretion basis and night, and this effect is its main clinical efficacy.
Though had therapeutic agent, still needed to the more effective broad-spectrum curing of gastrointestinal disease.For example, need safe and effective procedure and compositions and be used for prevention, treatment and control gastroenteropathy and not having side effects and deleterious drug-drug interactions.
3. summary of the invention
The biological action that the present invention includes by three kinds of different parts prevents, treats or control gastroenteropathy, promptly to 5-HT 3Receptor, 5-HT 4Receptor and H 2The effect of receptor or proton pump.The purposes of this triple role is considered to provide beat all good treatment characteristic.Compare with the purposes in any one site that acts on three sites separately, it is stronger to use triple role treatment toxicity effect lower and/or prevention, treatment and control gastroenteropathy.
In one embodiment, use three kinds of treatment reagent or chemical compound, one of them provides 5-HT 3Effect, the another kind of receptor provide 5-HT 4The effect of receptor, the third is proton pump inhibitor or H 2Receptor antagonist.For example, in preferred embodiments, use cisapride, ondansetron and proton pump inhibitor or H 2Receptor antagonist prevents, treats or control gastroenteropathy.In a preferred embodiment, (+) cisapride that Application Optics is pure or optically pure (-) cisapride or its officinal salt, optically pure R (+) ondansetron or its officinal salt and proton pump inhibitor or H 2Receptor antagonist.
In another embodiment, the present invention relates to use that two or more reagent or chemical compound are collaborative provides 5-HT 3Receptor, 5-HT 4Receptor and H 2The triple role of receptor or proton pump.In preferred embodiments, use two kinds of reagent or chemical compound, a kind of providing to 5-HT 3Receptor and 5-HT 4The dual function of receptor, another kind provides H 2The effect of receptor or proton pump.For example, in this preferred embodiment, cisapride or its officinal salt fall in optical voidness (+), and (it has 5-HT concurrently 3Receptor and 5-HT 4Receptor active) and proton pump inhibitor or H 2Receptor antagonist is used to prevention, treatment or control gastroenteropathy.
The invention still further relates to two kinds of independent separated drug compositionss in the application that prevents, treats or control among the patient who suffers from gastroenteropathy or its symptom, one of them contains the optical voidness (+) for the treatment of effective dose and falls cisapride or its officinal salt, and another kind contains proton pump inhibitor or the H that treats effective dose 2Receptor antagonist.
Another kind of selectable mode is, the present invention also comprises pharmaceutical composition, and it contains optically pure (+) and falls cisapride or its officinal salt and a kind of proton pump inhibitor or H 2The associating of receptor antagonist.Single unit dosage forms like this contains about 0.5mg of being present in the suitable carrier and falls extremely about 200mg proton pump inhibitor or about 1mg about 2400mg H extremely of cisapride or its officinal salt and about 1mg to about 500mg optically pure (+) 2Receptor antagonist.
Pharmaceutical composition of the present invention and method, particularly those contain that the pharmaceutical composition of cisapride or its officinal salt falls in the optical voidness (+) for the treatment of effective dose and method can be used for prevention or alleviate the gastroenteropathy symptom, can reduce or avoid by taking for example conventional 5-HT of conventional therapy agent simultaneously 3Receptor antagonist, 5-HT 4Receptor stimulating agent or antagonist, H 2The side effect that receptor antagonist and proton pump inhibitor brought.And, the compositions and methods of the invention comprise treatment, prevention or control gastroenteropathy and reduce simultaneously or avoid deleterious drug-drug interactions, known to using existing commercially available prod for example during the raceme cisapride, this interaction can appear.
4. detailed Description Of The Invention
The present invention includes prevention, treatment or the control of gastroenteropathy, its approach is by the biological action three different loci, promptly acts on 5-HT 3Receptor, 5-HT 4Receptor, and H 2Receptor or proton pump (for example suppress H +-K +-ATP enzyme system).The application of this triple sites effect is considered to provide the treatment than conventional gastroenteropathy that surprising good treatment characteristic is arranged.Compare with the reagent of using any one site act on three sites separately, using the triple role treatment can be safer and/or more effectively prevent, treat and control gastroenteropathy.
More particularly, the invention still further relates to the application in prevention, treatment or control gastroenteropathy or its symptom of at least three kinds of reagent or chemical compound, wherein a kind of 5-HT that acts on 3Receptor, another kind act on 5-HT 4Receptor, the third acts on proton pump system or H 2Receptor.Preferably, these three kinds of chemical compounds are cisapride, ondansetron and proton pump inhibitor or H 2Receptor antagonist.More preferably, these three kinds of chemical compounds are optically pure (+) cisapride or optically pure (-) cisapride or its officinal salt, optically pure R (+) ondansetron or its officinal salt and proton pump inhibitor or H 2Receptor antagonist.
The invention still further relates to provide and act on 5-HT 3Receptor, 5-HT 4Receptor and H 2At least two kinds of reagent of the triple role of receptor or proton pump mechanism or the chemical compound synergistic application in prevention, treatment or control gastroenteropathy.Preferably, use two kinds of reagent or chemical compound, a kind of 5-HT that is provided at 3Receptor and 5-HT 4The dual function at receptor place, another kind is provided at H 2The effect at receptor or proton pump system place.More preferably, these two kinds of reagent or chemical compound are that cisapride or its officinal salt and H fall in optically pure (+) 3Receptor antagonist or proton pump inhibitor.
Can include but not limited to upper and lower gastrointestinal system disease, stomach-esophageal regurgitation disease (" GERD "), vomiting, gastrointestinal movement malfunction, gastrointestinal ulceration, pathologic supersecretion disease and hyperchlorhydria with the gastroenteropathy of the present composition and method treatment.Described gastroenteropathy includes but not limited to also that dyspepsia, gastroparesis, constipation, post operative ileus, the false obstruction of intestinal, gastric ulcer, duodenal ulcer, heartburn, hyperchlorhydria dyspepsia, aggressivity esophagitis, stomach turn sour, stomach upset and Zuo-Ai syndrome.
In the most preferred embodiment, the present invention relates to optical voidness (+) and fall cisapride or its officinal salt and at least a proton pump inhibitor or H 2The application of receptor antagonist in prevention, treatment or control gastroenteropathy or its symptom.Although be noted that it is preferred that cisapride falls in optical voidness (+), in method and composition of the present invention, can use that cisapride falls in raceme or its officinal salt replaces optical voidness (+) to fall cisapride.Similarly, if be fit to, the scheme of selecting as for the election can be used proton pump inhibitor or H 2The optical voidness stereoisomer of antagonist or its active metabolite with and officinal salt.This paper only enumerates specific embodiment in illustrational mode.
Be not bound by theory, it is believed that to use to have 5-HT 3Receptor antagonist and 5-HT 4The reagent of receptor stimulating agent double activity or chemical compound and proton pump inhibitor or H 2Receptor antagonist provides triple role, and this application produces unexpectedly: the more obviously minimizing of dosage correlation effect, side effect, the good treatment that causes by synergistic activity and thus due to high therapeutic index.For example, optical voidness (+) falls cisapride and has 5-HT 3Receptor antagonist and 5-HT 4The receptor stimulating agent double activity, when with proton pump inhibitor or H 2To have triple role during the receptor antagonist use in conjunction.Therefore, with independent application 5-HT 3Receptor antagonist, 5-HT 4Receptor stimulating agent, has 5-HT 3Receptor antagonist and 5-HT 4The reagent of receptor stimulating agent double activity or chemical compound, proton pump inhibitor or H 2Receptor antagonist is compared, and more needs to use the compositions and methods of the invention.
According to the present invention, cisapride or its officinal salt and proton pump inhibitor or H fall in use in conjunction optical voidness (+) 2Receptor antagonist prevention, treatment or control gastroenteropathy are considered to reduce or to avoid and the existing for example relevant side effect of raceme cisapride of product that is used for the treatment of gastroenteropathy.In addition, think that also this embodiment is used to reduce or avoid the bad drug-drug interactions relevant with the raceme cisapride.
The invention still further relates to prevention, treatment or control by 5-HT 3Receptor, 5-HT 4Receptor or proton pump or H 2The proton pump inhibitor or the H of cisapride or its officinal salt and treatment effective dose falls in the method for the bad disease that causes of receptor function controlling, this method by the optical voidness (+) of taking the treatment effective dose 2Receptor antagonist.
The invention still further relates to the method for prevention, treatment or control GERD, vomiting, gastrointestinal movement malfunction, gastrointestinal ulceration, pathologic supersecretion disease or hyperchlorhydria, comprising: cisapride or its officinal salt and proton pump inhibitor or H fall in the optical voidness (+) of taking the treatment effective dose to the patient 2Receptor antagonist.In specific embodiment, the invention still further relates to that these reagent of use in conjunction are used for that prevention, treatment or control aggressivity esophagitis, dyspepsia, gastroparesis, constipation, post operative ileus, the false obstruction of intestinal, gastric ulcer, duodenal ulcer, heartburn, hyperchlorhydria dyspepsia, aggressivity esophagitis, stomach turn sour, stomach-ache and Zuo-Ai syndrome.
Relate to the present invention that triple role treatment uses and can comprise randomly that also one or more other becoming known for treat the application of the treatment reagent of gastroenteropathy.The example of described other therapeutic agent includes but not limited to hydroxyzine (ANTARAX ), diphenhydramine (BENADRYLPARENTAREL ), prochlorperazine (COMPAZINE ), dronabinol (MARINOL ), promethazine (PHENERGAN ), meclizine (ANTIVERT ), trimethobenzamide (TIGAN ), thiethylperazine (TORECAN ), perphenazine (TRILAFON ) and sucralfate (CARAFATE ) etc., when suitable, also comprise its optically pure stereoisomer or its active metabolite.
In the inventive method used two or more therapeutic agents can be simultaneously, continuously or administering drug combinations, that is to say that cisapride or its officinal salt and proton pump inhibitor or H fall in optical voidness (+) 2Receptor antagonist and optional other therapeutic agent can administering drug combinations, while but administration or successive administration independently.
Method and composition of the present invention is believed to provide the advantage that reduces or avoid the side effect relevant with the existing method and composition that is used for the treatment of gastroenteropathy.Referring to: Physician ' s Desk Reference , Medical Economics Co., Inc., the 52nd edition (1998 and 1999).
Term used herein " disadvantageous effect " and " deleterious side effect " include but not limited to arrhythmia, cardiac conduction obstacle, appetite excitement, weight increase, calmness, gastrointestinal tract misery, headache, xerostomia, constipation, diarrhoea and drug-drug interactions.Term " arrhythmia " includes but not limited to ventricle tachycardia, torsades de points, Q TProlong and ventricular fibrillation.
Term used herein " gastroenteropathy " includes but not limited to that gastrointestinal movement malfunction, GERD, vomiting, gastrointestinal ulceration, pathologic gastroxia disease, hyperchlorhydria, aggressivity esophagitis, dyspepsia, gastroparesis, constipation, postoperative ileus, intestinal pseudo-obstruction, gastric ulcer, duodenal ulcer, heartburn, hyperchlorhydria dyspepsia, aggressivity esophagitis, stomach turn sour, stomach upset and Zuo-Ai syndrome.
Term used herein " patient " is meant particularly people of mammal.
Term used herein " raceme " is meant (+) and (-) enantiomeric mixture that existed in about 1: 1 with ratio.
Term used herein " optical voidness " refers to contain based on the active component gross weight mixture of the required stereoisomer more than 90% weight of having an appointment, wherein required stereoisomer is preferably greater than about 95% weight, more preferably greater than about 99% weight, for example when using cisapride, described active component gross weight refers to (+) cisapride.Term used herein " be substantially devoid of " refer to less than about 10% weight, preferably less than about 5% weight, be more preferably less than the non-required stereoisomer of wanting of about 1% weight, for example cisapride falls in (-).
Term " 5-HT used herein 3Receptor antagonist " refer to can reversibility be attached to the chemical compound of 3-type 5-hydroxytryptamine receptor.5-HT 3Receptor antagonist includes but not limited to granisetron (KYTRIL ), metoclopramide (REGLAN ), ondansetron (ZOFRAN ), renzapride, zacopride and tropisetron, can be optical voidness stereoisomer or its active metabolite of above-mentioned substance when suitable.
Term " 5-HT used herein 4Receptor stimulating agent " refer to that the energy reversibility is incorporated into the chemical compound of 4-type 5-hydroxytryptamine receptor.5-HT 4Receptor stimulating agent includes but not limited to fall cisapride and cisapride, is its optical voidness stereoisomer or its active metabolite when suitable.
Term used herein " proton pump " refers to H +-K +-ATP enzyme, a kind of membrane-bound enzyme, it helps H +Contrary Concentraton gradient is striden the active transport of film.
Term used herein " proton pump inhibitor " refers to any by suppressing H on the eccrine surface of gastric epithelial cell +-K +-ATP enzyme system suppresses or suppresses the reagent or the chemical compound of gastric acid secretion.Proton pump inhibitor includes but not limited to draw azole (prazole) derivant, and for example omeprazole, lansoprazole, pantoprazole, Lapie draw azoles (rabeprazole), when suitable, can be its optical voidness stereoisomer for example optical voidness (+) lansoprazole, optical voidness (-) lansoprazole, optical voidness (+) omeprazole, optical voidness (-) omeprazole, optical voidness (+) Lapie draw azoles, optical voidness (-) Lapie to draw azoles, optical voidness (+) pantoprazole and optical voidness (-) pantoprazole, or its active metabolite.The active metabolite that is suitable for proton pump inhibitor of the present invention includes but not limited to the carboxylic acid derivates and the demethylation pantoprazole of 5-Hydroxyomeprazole, Hydroxylansoprazole, omeprazole, when suitable, can use its optically pure stereoisomer.For example, can be according to synthetic method known to a person of ordinary skill in the art, especially according to US 4,544,750,4,620,008,4,620,008,4,758,579,5,045,552,5,374,730,5,386,032,5,470,983 and 5,502,195 preparation omeprazoles, lansoprazole, pantoprazole and Lapie draw azoles, and the content of these patent disclosures is hereby incorporated by.
Term " H used herein 2Receptor antagonist " referring to can competitive inhibition histamine and H 2Any agent of acceptor interaction or chemical compound.H 2Receptor antagonist includes but not limited to cimetidine, famotidine, ranitidine, ZL-101, can be its optical voidness stereoisomer or its active metabolite when suitable.H 2The active metabolite of receptor antagonist includes but not limited to the single demethylation ZL-101 of N2-and can be its optical activity stereoisomer when suitable.
ZL-101 can particularly can adopt US 5,541 according to the known synthetic method of those of ordinary skills, 335 and US 5,700,945 in disclosed method preparation, its disclosed content is hereby incorporated by.Ranitidine can be synthetic according to the known method of those of ordinary skills, particularly can adopt US 5,118, the preparation of 813 disclosed methods, and its disclosed content is hereby incorporated by.Cimetidine can particularly can adopt US 4,413 according to the preparation of the known method of those of ordinary skills, and 129, US4,855,439, US4,886,910, US 4,886,912 and US 5,118,813 disclosed methods, its disclosed content is hereby incorporated by.In addition, famotidine can be according to the known synthetic method preparation of those of ordinary skills, and for example according to ContactDermatitis such as Guimaraens, 31 (4): 259 (1994) the middle methods of describing prepare.
The disease of the present invention's prevention, treatment or control can be referring to Stedman ' s MedicalDictionary the 26th edition, Williams and Wilkins (1995).
Term used herein " stomach-esophageal regurgitation disease " or " GRED " are defined as flowing into the disease that esophagus is a feature so that content in the stomach is counter.
It is the disease of feature that term used herein " gastrointestinal ulceration " is defined as with the gastrointestinal tract wall surface infringement being arranged, and it is caused by the surface texture loss, usually with inflammation.Gastrointestinal ulceration includes but not limited to duodenal ulcer and gastric ulcer.
What term used herein " aggressivity esophagitis " was defined as being caused by the anti-stream of acid stomach content is the disease of feature with the lower esophagus inflammation, and it is caused by bottom sphincter of gullet malfunction usually.
It is the disease of feature that term used herein " dyspepsia " is defined as with digestive function or function infringement, and it can show as constitutional gastrointestinal dysfunction symptom or for example appendicitis, gallbladder are lacked of proper care or the caused syndrome of malnutrition by other disease.
Term used herein " gastroparesis " is defined as gastroparalysis, and it is caused that by the stomach dyskinesia perhaps it is defined as for example complication of diabetes, SPS, anorexia nervosa or myotonia atrophica of some diseases.
Term used herein " constipation " is defined as with not often or be difficult to the disease that defecation is a feature, and for example myenteron meat is nervous lacks or the enterospasm state is caused by some diseases for it.
Term used herein " postoperative ileus " is defined as being blocked by the operation back muscular tone caused enteral that breaks.
Term used herein " prevention " and " preventing " are respectively defined as the generation that stops or hinder and stop or hinder patient disease or disease, wherein said patient has and suffers from the such disease or the danger of disease, described patient includes but not limited to the to suffer from stress state patient of (stress).
Term used herein " intestinal pseudo-obstruction " is defined as with constipation, angor and vomiting but does not have physical property to block is the disease of feature.
It is the disease of feature that term used herein " hyperchlorhydria " is defined as high unusually with acidity in the gastric juice.
Term used herein " treatment effective dose " be defined as that therapeutic agent is used separately or with the other medicines use in conjunction prevention, treatment to be provided or to control the amount of the therapeutic agent of gastroenteropathy therapeutic effect, wherein said gastroenteropathy includes but not limited to gastrointestinal movement malfunction, GERD, vomiting, gastrointestinal ulceration, pathologic gastroxia disease, hyperchlorhydria or its symptom.Can use different treatment effective doses for various diseases, know easily as those of ordinary skills.
Optical voidness (+) falls cisapride and can be obtained by the cisapride racemic mixture, its chemosynthesis can be according to disclosed european patent application 0,076 on April 13 nineteen eighty-three, and the method for 530A2 record is carried out, perhaps according to US 4,962,115,5,057,525 or 5, the method of 137,896 records is carried out, and the disclosed content of these documents is hereby incorporated by.Also can wait Drug Development Res., 8:225-232 (1986) referring to Van Daele.At Meuldermans, Drug Metab.Dispos. such as W, 16 (3): 410-419 (1988) and Meuldermans, W. waits Drug Metab.Dispos., and 16 (3): put down in writing the cisapride metabolism for falling cisapride among the 403-409 (1988).Those of ordinary skills know that also the preparation method of cisapride falls in raceme, particularly can be referring to the EP0 of Van Daele, and 076,530A2 and US 5,137,896, the disclosed content of these patents is hereby incorporated by.For example the active fractionation of Application Optics is sour by splitting enantiomer prepares chipal compounds discussed in this article from racemic mixture optical voidness stereoisomer also can to use usual manner.Those of ordinary skills also know the method for splitting of racemic compound, especially can join and exempt from: Jacques, Enantimers such as J., Racemates and Resolutions, Wiley-Interscience New York (1981); Wilen, S.H. waits Tetrahedron, 33:2725 (1977); Eliel, E.L.StereochemisTry of Carbon Compounds, McGraw-Hill, NY, (1962); Wilen, S.H.Tables of Resolving Agentsand Optical Resolutions, E.L.Eliel, editor Univ.of Notre DamePress, Notre Dame, IN, the 268th page (1972).
Except using above-mentioned isolation technics, also can use method known to a person of ordinary skill in the art, by the optically pure chemical compound of the synthetic preparation of stereospecificity.The synthetic product that can produce high enantiomeric purity of chirality.Yet in some cases, the enantiomeric purity of product is not high enough.Those skilled in the art understand: can use above-mentioned separation method and further improve its enantiomeric purity to splitting by the synthetic active stereoisomer that obtains of chirality.
For example, also can split and fall the cisapride mixture from raceme and prepare optically pure (+) and fall cisapride by enzymes biocatalysis.This synthetic be known for those of ordinary skills, especially can be referring to US 5,057,427 and 5,077,217, the content of these patent disclosures is hereby incorporated by.
In the acute or chronic control of disease described herein and symptom, (for example cisapride, 5-HT fall to described active component in (+) 3Antagonist, 5-HT 4Agonist or antagonist, proton pump inhibitor or H 2Receptor antagonist) preventive dose or therapeutic dose size can change according to the character of the disease of preventing, treating or controlling and the order of severity and route of administration.For example, can adopt oral, mucosa (comprising rectum), parenteral (comprising subcutaneous, intramuscular, bolus injection and intravenous injection), Sublingual, percutaneous, intranasal and the mode administration such as suck.Used dosage form comprises tablet, capsule, lozenge, lozenge, dispersion, suspensoid, suppository, solution, capsule, soft elastic gelatin capsule and patch etc.Used dosage and even administration frequency also can adjust according to age, body weight and each reaction.Those skilled in the art consider to select suitable dosage regimen easily after the above-mentioned factor.
As a rule, the 5-HT that is used for the treatment of described disease 3Receptor antagonist, 5-HT 4Receptor stimulating agent or 5-HT is provided 3Receptor and 5-HT 4Accumulated dose every day of the therapeutic agent of receptor dual function is the about 500mg of about 0.5mg-, the preferably about 350mg of about 1mg-, the about 250mg of 2mg-more preferably from about.
Those skilled in the art determine suitable dosage every day of proton pump inhibitor easily.As a rule, total dose range every day for the treatment of the proton pump inhibitor (for example lansoprazole, pantoprazole, Lapie draw azoles, omeprazole or its optical voidness stereoisomer or its active metabolite) of described disease is the about 200mg of about 1mg-, the preferably about 150mg of about 5mg-, the about 100mg of 10mg-more preferably from about.
In addition, those skilled in the art determine H easily 2Suitable dosage range every day of receptor antagonist.Present used known H 2The receptor antagonist suitable dose can be referring to for example Physician ' s Desk Reference , Medical Economics Co., Inc., the 52nd edition (1999).For example, the used about 800mg of the oral about 1mg-of dosage range every day of ranitidine, the preferably about 600mg of about 100mg-, the about 500mg of 250mg-more preferably from about.Oral every day of the dosage range of cimetidine is the about 2400mg of about 1mg-, the preferably about 1600mg of about 400mg-, the about 1000mg of 600mg-more preferably from about.Oral every day of the dosage range of famotidine is the about 200mg of about 1mg-, the preferably about 80mg of about 10mg-, the about 50mg of 15mg-more preferably from about.Oral every day of the dosage range of ZL-101 is the about 600mg of about 1mg-, the preferably about 500mg of about 50mg-, the about 350mg of 250mg-more preferably from about.
When control patient symptom, the treatment beginning can by than low dosage for example the administration about 10mg of about 0.5mg-(+) cisapride and about 5mg proton pump inhibitor of about 1mg-or the about 5mg H of about 1mg-fall 2Receptor antagonist increases to up to the dosage of recommending or high dose more every day according to patient's combined reaction then again.In addition,, recommend during beginning to use low dosage, should carry out titration according to individual reaction and blood content then for the aged patient of child, over-65s and the patient of those hepatic and kidney function obstacles.In some cases, may also need to adopt each active component dosage outside the scope described herein, this it will be apparent to those skilled in the art that.In addition, should be noted that: according to each reaction, how and when clinicist or physician-in-charge know interrupts, adjustment or stopped treatment.
Be used for pharmaceutical composition of the present invention and can contain 5-HT 3Receptor antagonist and 5-HT 4Receptor stimulating agent or 5-HT is provided 3Receptor and 5-HT 4The therapeutic agent of receptor dual function and contain proton pump inhibitor or H 2Receptor antagonist is as active component, and described compositions may also contain pharmaceutically suitable carrier and other optional therapeutic component.
In one embodiment, described pharmaceutical composition contains three kinds of therapeutic agent: 5-HT 3Receptor antagonist and 5-HT 4Receptor stimulating agent and proton pump inhibitor or H 2Receptor antagonist can also contain pharmaceutically suitable carrier and other optional therapeutic component.In preferred embodiments, this pharmaceutical composition contains two kinds of therapeutic agents, a kind of 5-HT that provides 3Receptor and 5-HT 4The dual function of receptor, another kind is proton pump inhibitor or H 2Receptor antagonist.
Term used herein " officinal salt " refers to the salt that obtained fully by pharmaceutically acceptable non-toxicity processed with acid, and these acid include but not limited to mineral acid, organic acid, solvate, hydrate or clathrate.The example of described mineral acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid and phosphoric acid.Appropriate organic can be selected from, for example, aliphatic carboxylic acid, aromatic carboxylic acids and organic sulfonic acid class, its object lesson are formic acid, acetic acid, propanoic acid, succinic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, isethionic acid, lactic acid, malic acid, galactosaccharic acid, tartaric acid, p-methyl benzenesulfonic acid, hydroxyacetic acid, glucuronic acid, maleic acid, furancarboxylic acid, glutamic acid, benzoic acid, ortho-aminobenzoic acid, salicylic acid, phenylacetic acid, mandelic acid, pounce on acid (pamoic acid), methanesulfonic acid, ethyl sulfonic acid, pantothenic acid, benzenesulfonic acid, stearic acid, sulfanilic acid, alginic acid and galacturonic acid etc.Particularly preferred acid is hydrobromic acid, hydrochloric acid, phosphoric acid and sulphuric acid.In one embodiment, 5-HT 3Receptor antagonist, 5-HT 4Receptor stimulating agent or 5-HT is provided 3Receptor antagonist and 5-HT 4The therapeutic agent of receptor stimulating agent dual function is with free alkali form or hydrate forms administration.For example, optically pure (+) falls cisapride with free alkali or hydrate forms administration.
The invention still further relates to the purposes of tart reactive compound or reagent, salt wherein can prepare with pharmaceutically useful non-toxic bases, and used alkali comprises organic base, inorganic base, solvate, hydrate or its clathrate.Described inorganic base includes but not limited to the slaine of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.Suitable organic base includes but not limited to N, N-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), lysine and procaine.
In actual applications, the active agent in the pharmaceutical composition of the present invention can be used as active component and fully mixes with pharmaceutically suitable carrier according to the conventional medicine hybrid technology.Described carrier can be various ways and contain multiple composition according to the dosage form of required administration.Compositions of the present invention includes but not limited to suspensoid, solution and elixir; Aerosol; Or excipient includes but not limited to starch, saccharide, microcrystalline Cellulose, diluent, granulation agent, lubricant, binding agent and disintegrating agent etc.Preferably, pharmaceutical composition is a peroral dosage form.Owing to be easy to administration, tablet and capsule are preferred dosage form, and it represents best oral unit dosage form, wherein the applying solid excipient substance.If desired, can carry out coating to tablet with standard water or non-aqueous solution technology.
Preferably, combination of oral medication of the present invention is pressed single or multiple administration, every day 1-4 time.Described peroral dosage form can be unit dosage forms easily, and can be according to the known any means preparation of pharmaceutical field.
The pharmaceutical composition of the present invention that is fit to oral administration can be dispersive pharmaceutical unit dosage forms, for example capsule, cachet, soft elastic gelatin capsule, tablet, capsule or aerosol spray, each dosage form contains the active component of scheduled volume, perhaps is powder or granule or the solution in water or on-aqueous liquid or suspensoid, oil in water emulsion or Water-In-Oil liquid emulsion.Described compositions can prepare according to the known any means of pharmaceutical field, but all methods comprise one or more active component and the blended step of carrier.As a rule, described preparation of compositions is as follows: active component and liquid-carrier or fine solid carrier or the two fully mixing equably, then, if desired, described product is made the shape that needs.Oral solid formulation than oral liquid more preferably.A kind of preferred oral solid formulation is a capsule, but most preferred oral solid formulation is a tablet.
For example, can be by randomly preparing tablet with one or more adjuvant compactings or press back.Compressed tablet can prepare like this: in suitable machine, free-flowing form for example powdery or granulous active component randomly with tablettings such as binding agent, lubricant, inert diluent, granulation agent, surfactant or dispersant.Moulded tablet can prepare like this: in suitable machine, the mixture press back of the powder compounds of getting wet with inert liquid diluent.Preferably, each tablet, cachet, caplet or capsule contain have an appointment 0.5mg to about 500mg optical voidness (+) cisapride falls, more preferably from about 1mg is to about 350mg, and contains extremely about 200mg proton pump inhibitor or the about 1mg about 2400mg H extremely of 1mg that has an appointment 2Receptor antagonist.
Can use conventional method well known in the art being suitable for the pharmaceutical composition that oral preparation of pharmaceutical compositions of the present invention becomes the soft elastic gelatin capsule unit dosage forms, referring to: Ebert for example, Pharm.Tech, 1 (5): 44-50 (1977).Soft elastic gelatin capsule has a soft spherical gelatin shell, and is slightly thicker than the shell of hard gelatin capsule, and for example glycerol, sorbitol or similar polyhydric alcohol make gelatin plasticising by adding plasticizer.Type by changing used gelatin and water and plasticizer dosage can change the hardness of gelatin shell.Soft gelatin shell can contain antiseptic for example methyl parahydroxybenzoate and propyl ester and sorbic acid, to prevent fungi growth.Described active component can dissolve or be suspended in liquid-carrier or the adjuvant, and wherein said carrier or adjuvant be vegetable oil or mineral oil, glycols for example polysorbate or its mixture of Polyethylene Glycol and propylene glycol, triglyceride, surfactant for example for example.
Except that top used regular dosage form, chemical compound of the present invention can also pass through controlled release mode or release device administration, and the mode that these modes are known for those of ordinary skills for example is disclosed in US 3,845,770; 3,916,899; 3,536,809; 3,598,123; With 4,008, in 719,5,674,553,5,059,595,5,591,767,5,120,548,5,073,543,5,639,476,5,354,556 and 5,733,566, these disclosed contents are hereby incorporated by.These pharmaceutical compositions make one or more active component controlled release or slow release, and wherein for example hydroxypropyl methylcellulose, other polymeric matrix, gel, permeable membrane, osmosis system, multiple coatings, microgranule, liposome or microsphere etc. or the mixture of using described material in varing proportions provide needed release characteristics to application accessory.Can easily select the known suitable controlled release preparation of those of ordinary skills (comprising preparation described herein) to be used for pharmaceutical composition of the present invention.Therefore, the present invention includes oral single unit dosage forms for example tablet, capsule, gelcaps and the caplets etc. that are fit to sustained release.
All controlled release drug products have common target promptly to be provided than corresponding non-controlled release product better medicament therapeutic effect.As situation ideally, the controlled release preparation of using optimal design in Drug therapy is characterised in that: use minimum Drug therapy or control disease in the shortest time.The advantage of controlled release preparation comprises: the 1) therapeutic activity of prolong drug; 2) reduce medicine frequency; With 3) enhancing patient compliance.
Most of controlled release preparations are designed to originally discharge the medication amount of the required therapeutic effect of rapid generation, are discharging the medicine of its surplus to keep the level of this therapeutic effect in a long time with continuing gradually.Keep constant drug level in the body in order to make, medicine must discharge with the speed that is equal to internal metabolism and drainage medication amount.
Sustained release that can be by various attractant stimulating activity compositions is pH, temperature, enzyme, water or other physiological condition or chemical compound for example.In the context of the invention, term " controlled release component " is defined as helping the chemical compound of active component sustained release or the mixture of chemical compound, and described chemical compound includes but not limited to polymer, polymeric matrix, gel, permeable membrane, liposome, microsphere etc.
Pharmaceutical composition of the present invention can also be prepared into the parenteral dosage forms of administrated by injection (subcutaneous, bolus injection, intramuscular injection or intravenous injection), and for example can be scattered in the unit dosage forms in multi-dose container or the ampoule.Such parenteral compositions can be suspending agent, solution or the Emulsion etc. that are in aqueous or the oiliness carrier, and except that active component, it also can contain one or more formula agents for example dispersant, suspending agent, stabilizing agent and antiseptic etc.
Another kind of route of administration is a transdermal release, for example through the administration of skin of abdomen paster.
The present invention also explains by the following example, describes chemical compound of the present invention and preparation of compositions and application thereof in detail.Obviously, for a person skilled in the art, can under the prerequisite that does not depart from purpose of the present invention and right, make many improvement to material of the present invention and method.
5. embodiment
5.1 embodiment 1: receptors bind
5-HT 3Receptor
Test raceme and fallen cisapride, raceme cisapride and their (+) and (-) stereoisomer and the 5-HT that derives from the N1E-115 cell 3The combination of receptor subtype (Cerep, Celle l ' Evescault, France).
After suitable part is cultivated, under vacuum, filter these goods fast with the GF/B glass fiber filter, use the ice-cold buffer washing by Brandel or Packard cell harvestor then.(LS6000 Beckman) measures in conjunction with radioactivity by liquid scintillation counting in using liquid flicker cocktail agent (preparation 989).
Combine the poor of the non-specific binding that is defined as total binding and mensuration in the presence of excessive unmarked part with the specificity radioligand of receptor.The result is expressed as the percent inhibition of specific binding that in the presence of described chemical compound, obtains.Use 3 * 10 -10M to 10 -5The concentration range of M is determined IC to obtain complete competition curve 50Value, this value is calculated through nonlinear regression analysis.Its result is shown in following table 3 and 4.
Use said method and can also test other active component for example granisetron, metoclopramide, ondansetron, renzapride, zacopride and tropisetron etc.
5-HT 4Receptor
Test raceme and fallen cisapride, raceme cisapride and their (+) and (-) stereoisomer and the 5-HT that derives from Cavia porcellus striata 4The combination of receptor subtype (Cerep, Celle l ' Evescault, France).
After suitable part is cultivated, under vacuum, filter these goods fast with the GF/B glass fiber filter, use the ice-cold buffer washing by Brandel or Packard cell harvestor then.(LS6000 Beckman) determines in conjunction with radioactivity by liquid scintillation counting in using liquid flicker cocktail agent (preparation 989).
Combine the poor of the non-specific binding that is defined as total binding and mensuration in the presence of excessive unmarked part with the specificity radioligand of receptor.The result is expressed as the percent inhibition of specific binding that in the presence of described chemical compound, obtains.Use 3 * 10 -10M to 10 -5The concentration range of M is determined IC to obtain complete competition curve 50Value, this value is calculated through nonlinear regression analysis.Its result is shown in following table 3 and 4.
Use said method and can also test for example material such as cisapride of other active component.
Table 3
Be attached to 5-HT 3And 5-HT 4The IC in site 50(nM) value compound 5-HT 35-HT 45-HT 3/ 5-HT 4Falling cisapride 8.2 686 0.012 (+) than (±) falls cisapride 4.5 331 0.014 (-) and falls cisapride 30.4 1,350 0.023
Table 4
Be attached to 5-HT 3And 5-HT 4The IC in site 50(nM) value compound 5-HT 35-HT 45-HT 3/ 5-HT 4Than (±) cisapride 365 169 2.2 (+) cisapride 310 340 0.9 (-) cisapride 2,790 199 14.0
Application also can be measured 5-HT based on the analysis that reactive compound is increased in the mice embryonic colloculi neuron medium ring AMP generative capacity of growing in the tissue culture 4The agonist activity of acceptor site (referring to Dumuis etc., N.S.Arch.Pharmacol., 340:403-410 (1989)).
5.2 embodiment 2: every content of oral formulations tablet formulation (mg)
A B C active component 5.0 10.0 25.0 (+) fall Cisapride Lansoprazole 5.0 15.0 30.0 lactose BP 57.0 92.0 107.0 starch BP 20.0 20.0 25.0 microcrystalline celluloses 10.0 10.0 10.0 hydrogenated vegetable oils 1.5 1.5 1.5 PVPs 1.5 1.5 1.5 compressing tablets and weigh 100.0 150.0 200.0
Cisapride is fallen in active component (+) and lansoprazole sieves with suitable sieve, then it is mixed with lactose until forming uniform mixture.Add the water of suitable volumes, then powder is granulated.After the drying, the granule that sieves mixes it with remaining adjuvant.Then the granule that obtains is pressed into the tablet of required form.The tablet that can prepare other intensity by ratio or the change tabletting weight that changes active component and adjuvant.
5.3 embodiment 3: every content of oral formulations tablet formulation (mg)
A B C active component 5.0 10.0 25.0 (+) fall Cisapride famotidine 10.0 20.0 40.0 lactose BP 38.5 73.5 43.5 starch BP 30.0 30.0 60.0 pregelatinized corn starch BP 15.0 15.0 30.0 dolomol BP 1.5 1.5 1.5 compressing tablets and weigh 100.0 150.0 540.0
Cisapride is fallen in active component (+) and famotidine sieves with suitable sieve, then it is mixed with lactose, starch and pregelatinized corn starch until forming uniform mixture.Add the water of suitable volumes, then powder is granulated.After the drying, the granule that sieves mixes it with remaining adjuvant.Then the granule that obtains is pressed into the tablet of required form.The tablet that can prepare other intensity by ratio or the change tabletting weight that changes active component and adjuvant.
5.4 embodiment 4: every content of formulation tablet formulation (mg)
A B C active component 5.0 10.0 25.0 (+) fall Cisapride lactose BP 48.5 43.5 78.5 starch BP 30.0 30.0 30.0 pregelatinized corn starch BP 15.0 15.0 15.0 dolomol BP 1.5 1.5 1.5 compressing tablets and weigh 100.0 100.0 150.0
With suitable sieve cisapride is fallen in active component (+) and sieve, then it is mixed with lactose, starch and pregelatinized corn starch until forming uniform mixture.Add the water of suitable volumes, then powder is granulated.After the drying, the granule that sieves mixes it with remaining adjuvant.Then the granule that obtains is pressed into the tablet of required form.The tablet that can prepare other intensity by ratio or the change tabletting weight that changes active component and adjuvant.
Now described the present invention by specific embodiment, obviously, for a person skilled in the art, can under the prerequisite that does not depart from the scope and spirit of the present invention described in the claim, make various variations and modification the present invention.These modifications also fall within the scope of the application's claim.

Claims (56)

1. treat the method for patient's gastrointestinal tract disease, it comprises: take one or more reagent or chemical compound or its optical voidness stereoisomer or its active metabolite or its officinal salt of treatment effective dose, wherein said reagent or chemical compound are simultaneously or act on 5-HT in order 3Receptor, 5-HT 4Receptor and proton pump or H 2Receptor.
2. treat the method for patient's gastrointestinal tract disease, it comprises: the antagonism 5-HT that takes the treatment effective dose 3Receptor and exciting 5-HT 4At least a proton pump inhibitor or the H of the reagent of receptor or chemical compound and treatment effective dose 2Receptor antagonist, or the optical voidness stereoisomer of these chemical compounds or reagent or its active metabolite or its officinal salt.
3. treat the method for patient's gastrointestinal tract disease, it comprises: take at least a proton pump inhibitor, the H that cisapride or its officinal salt and treatment effective dose fall in treatment (+) effective dose, that be substantially free of (-) stereoisomer to the patient 2Receptor antagonist, or its optical voidness stereoisomer or its active metabolite or its officinal salt.
4. the method for claim 3, wherein said patient behaves.
5. the method for claim 3, wherein gastroenteropathy is the gastrointestinal movement malfunction.
6. the method for claim 5, wherein the gastrointestinal movement malfunction is selected from dyspepsia, gastroparesis, constipation, postoperative ileus and intestinal pseudo-obstruction.
7. the method for claim 3, wherein gastroenteropathy is stomach-esophageal regurgitation disease, vomiting, gastrointestinal ulceration, pathologic supersecretion disease and hyperchlorhydria.
8. the method for claim 7, wherein pathologic supersecretion disease is Zuo-Ai syndrome.
9. the method for claim 7, wherein hyperchlorhydria is selected from: heartburn, hyperchlorhydria dyspepsia, stomach turn sour, aggressivity esophagitis and stomach upset.
10. the method for claim 3, wherein (+) to fall the dose of cisapride be the about 500mg of about 0.5mg-.
11. the method for claim 10, wherein (+) to fall the dose of cisapride be the about 350mg of about 1mg-.
12. the method for claim 3, wherein take proton pump inhibitor, described proton pump inhibitor is selected from: omeprazole, lansoprazole, Lapie draw azoles, pantoprazole, 5-Hydroxyomeprazole, demethylation pantoprazole, Hydroxylansoprazole and optical voidness stereoisomer thereof.
13. the method for claim 12, wherein the consumption of proton pump inhibitor is the about 200mg of about 1mg-.
14. the method for claim 13, wherein the consumption of proton pump inhibitor is the about 150mg of about 5mg-.
15. the method for claim 3 is wherein taken H 2Receptor antagonist, described H 2Receptor antagonist is selected from cimetidine, ranitidine, famotidine, ZL-101 and optical voidness stereoisomer thereof or its active metabolite.
16. the method for claim 15, wherein H 2The consumption of receptor antagonist is the about 2400mg of about 1mg-.
17. the method for claim 3, at least a in cisapride and the proton pump inhibitor falls in wherein oral take (+).
18. the method for claim 17 is wherein fallen cisapride and proton pump with tablet or oral take (+) of capsule form.
19. the method for claim 3, cisapride and H fall in wherein oral take (+) 2At least a in the receptor antagonist.
20. the method for claim 3 is wherein proton pump inhibitor or H 2Receptor antagonist falls cisapride with (+) and takes by parenteral, percutaneous, rectum or Sublingual.
21. the method for claim 3, it comprises: proton pump inhibitor or H 2Receptor antagonist falls the cisapride while with (+) or takes in order.
22. the method for treatment patient's gastrointestinal tract motion function obstacle, it comprises: (+) that be substantially free of (-) stereoisomer of described patient being taken the treatment effective dose falls cisapride or its officinal salt and treats at least a proton pump inhibitor, the H of effective dose 2Receptor antagonist, or its optical voidness stereoisomer or its active metabolite or its officinal salt.
23. the method for treatment patient vomiting, it comprises: take at least a proton pump inhibitor, the H that cisapride or its officinal salt and treatment effective dose fall in (+) that be substantially free of (-) stereoisomer for the treatment of effective dose for the patient of this prevention of described needs, treatment or control 2Receptor antagonist, or its optical voidness stereoisomer or its active metabolite or its officinal salt.
24. the method for treatment patient stomach-esophageal regurgitation disease, it comprises: at least a proton pump inhibitor, the H of cisapride or its officinal salt and treatment effective dose falls in (+) that be substantially free of (-) stereoisomer of taking the treatment effective dose 2Receptor antagonist, or its optical voidness stereoisomer or its active metabolite or its officinal salt.
25. the method for treatment patient stomach-esophageal regurgitation disease, it comprises that patient to this treatment of needs takes the treatment effective dose: (a) cisapride or its officinal salt or its optical voidness stereoisomer; (b) ondansetron or its officinal salt or its optical voidness stereoisomer; (c) at least a proton pump inhibitor, the H of treatment effective dose 2Receptor antagonist or its optical voidness stereoisomer or its active metabolite or its officinal salt.
26. the method for claim 25 is wherein taken optical voidness (+) cisapride or optical voidness (-) cisapride or its officinal salt.
27. the method for claim 25 or 26 is wherein taken optical voidness R (+) ondansetron.
28. the method for claim 25, wherein the proton pump inhibitor of being taken is selected from carboxylic acid derivates and the demethylation pantoprazole that omeprazole, lansoprazole, pantoprazole, Lapie draw azoles, hydroxyl-omeprazole, Hydroxylansoprazole, omeprazole.
29. the method for claim 25, wherein the dose of proton pump inhibitor is that about 1mg is to about 200mg.
30. the method for claim 25, the wherein H that is taken 2Receptor antagonist is selected from cimetidine, famotidine, ranitidine, ZL-101 and N2-demethylation ZL-101.
31. the method for claim 25, wherein H 2The dose of receptor antagonist is the about 2400mg of about 1mg-.
32. the method for claim 25 is wherein orally taken at least a in optical voidness (+) cisapride, optical voidness (-) cisapride, optical voidness R (+) ondansetron and the proton pump inhibitor.
33. the method for claim 25, wherein oral cisapride, optical voidness R (+) ondansetron and the H of taking 2At least a in the receptor antagonist.
34. the method for prevention or control patient's gastrointestinal tract disease, it comprises: the 5-HT that takes the treatment effective dose to the patient of needs prevention or control 3Receptor antagonist, 5-HT 4Receptor stimulating agent and H 2At least a or its optical voidness stereoisomer or its active metabolite or its officinal salt in receptor antagonist or the proton pump inhibitor.
35. the method for prevention or control patient's gastrointestinal tract disease, it comprises: the 5-HT that acts on that takes the treatment effective dose 3Receptor and 5-HT 4The H of the reagent of receptor or chemical compound and treatment effective dose 2At least a or its optical voidness stereoisomer or its active metabolite or its officinal salt in receptor or the proton pump.
36. the method for prevention or control patient's gastrointestinal tract disease, it comprises: proton pump inhibitor, the H of cisapride or its officinal salt and treatment effective dose falls in (+) that be substantially devoid of (-) stereoisomer that takes the treatment effective dose for described patient 2At least a or its optical voidness stereoisomer or its active metabolite or its officinal salt in the receptor antagonist.
37. the method for prevention or control patient's gastrointestinal tract motion function obstacle, it comprises: proton pump inhibitor, the H of cisapride or its officinal salt and treatment effective dose falls in (+) that be substantially devoid of (-) stereoisomer that takes the treatment effective dose for described patient 2At least a in receptor antagonist or its optical voidness stereoisomer or its active metabolite or its officinal salt.
38. the method for prevention or control patient vomiting, it comprises: take proton pump inhibitor, the H that cisapride or its officinal salt and treatment effective dose fall in (+) that be substantially devoid of (-) stereoisomer for the treatment of effective dose for the described patient of this prevention of needs, treatment or control 2At least a or its optical voidness stereoisomer or its active metabolite or its officinal salt in the receptor antagonist.
39. the method for prevention or control patient stomach-esophageal regurgitation disease, it comprises: proton pump inhibitor, the H of cisapride or its officinal salt and treatment effective dose falls in (+) that be substantially devoid of (-) stereoisomer that takes the treatment effective dose for described patient 2At least a or its optical voidness stereoisomer or its active metabolite or its officinal salt in the receptor antagonist.
40. the method for prevention or control patient stomach-esophageal regurgitation disease, it comprises; Take (a) of treatment effective dose for the patient who needs this prevention or control: cisapride or its optical voidness stereoisomer or its officinal salt; (b) ondansetron or its officinal salt or its optical voidness stereoisomer; (c) proton pump inhibitor, the H of treatment effective dose 2At least a or its optical voidness stereoisomer or its active metabolite or its officinal salt in the receptor antagonist.
41. the method for claim 40 is wherein taken optical voidness (+) cisapride or optical voidness (-) cisapride or its officinal salt.
42. the method for claim 40 is wherein taken optical voidness R (+) ondansetron or its officinal salt.
43. the method for claim 40, wherein the proton pump inhibitor of being taken is selected from: omeprazole, lansoprazole, pantoprazole, Lapie draw the carboxylic acid derivates and the demethylation pantoprazole of azoles, 5-Hydroxyomeprazole, Hydroxylansoprazole, omeprazole.
44. the method for claim 40, wherein the dose of proton pump inhibitor is the about 200mg of about 1mg-.
45. the method for claim 40, the wherein H that is taken 2Receptor antagonist is selected from cimetidine, famotidine, ranitidine, ZL-101 and N2-demethylation ZL-101.
46. the method for claim 40, wherein H 2The dose of receptor antagonist is the about 2400mg of about 1mg-.
47. the method for claim 40 is wherein orally taken at least a in cisapride, R (+) ondansetron and the proton pump inhibitor.
48. the method for claim 40, wherein oral cisapride, R (+) ondansetron and the H of taking 2At least a in the receptor antagonist.
49. be applicable to treatment gastroenteropathy patient's pharmaceutical composition, it comprises: cisapride or its officinal salt fall in (+) that be substantially devoid of (-) stereoisomer of treatment effective dose; Proton pump inhibitor, H with the treatment effective dose 2At least a or its optical voidness stereoisomer or its active metabolite in the receptor antagonist, or its officinal salt.
50. the pharmaceutical composition of claim 49 wherein contains proton pump inhibitor, it is selected from omeprazole, pantoprazole, Lapie and draws azoles, lansoprazole, 5-Hydroxyomeprazole, Hydroxylansoprazole, omeprazole carboxylic acid derivates and demethylation pantoprazole.
51. the pharmaceutical composition of claim 49 wherein contains H 2Receptor antagonist, it is selected from cimetidine, ranitidine, famotidine, ZL-101 and N2-demethylation ZL-101.
52. be applicable to treatment gastroenteropathy patient's pharmaceutical composition, it comprises: (a) cisapride optical voidness stereoisomer or its officinal salt of treatment effective dose; (b) optical voidness R (+) ondansetron or its officinal salt of treatment effective dose; (c) proton pump inhibitor, the H of treatment effective dose 2At least a or its optical voidness stereoisomer or its active metabolite or its officinal salt in the receptor antagonist.
53. the pharmaceutical composition of claim 52 wherein contains proton pump inhibitor, it is selected from carboxylic acid derivates and demethylation pantoprazole that omeprazole, pantoprazole, Lapie draw azoles, lansoprazole, 5-Hydroxyomeprazole, Hydroxylansoprazole, omeprazole.
54. the pharmaceutical composition of claim 52 wherein contains H 2Proton pump inhibitor, it is selected from cimetidine, ranitidine, famotidine, ZL-101 and N2-demethylation ZL-101.
55. the method for claim 12, wherein proton pump inhibitor is: optical voidness (+) pantoprazole, optical voidness (-) pantoprazole, optical voidness (+) Lapie draw azoles, optical voidness (-) Lapie to draw azoles, optical voidness (+) lansoprazole, optical voidness (-) lansoprazole, optical voidness (+) omeprazole or optical voidness (-) omeprazole.
56. the pharmaceutical composition of claim 50 or 53, wherein proton pump inhibitor is: (+) pantoprazole, optical voidness (-) pantoprazole, optical voidness (+) Lapie draw azoles, optical voidness (-) Lapie to draw azoles, optical voidness (+) lansoprazole, optical voidness (-) lansoprazole, optical voidness (+) omeprazole or optical voidness (-) omeprazole.
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